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Literature summary for 1.4.1.1 extracted from

  • Jeong, J.A.; Oh, J.I.
    Alanine dehydrogenases in mycobacteria (2019), J. Microbiol., 57, 81-92 .
    View publication on PubMed
Search for more literature for 1.4.1.1

Application

Application Comment Organism
medicine an Ald-specific inhibitor and respiration inhibitory antitubercular drugs, such as Q203 and BDQ, are likely to enable more efficient therapies for tuberculosis Mycolicibacterium smegmatis
medicine plausible application of Ald inhibitors for treatment of tuberculosis. An Ald-specific inhibitor and respiration inhibitory antitubercular drugs, such as Q203 and BDQ, are likely to enable more efficient therapies for tuberculosis Mycobacterium tuberculosis

Cloned(Commentary)

Cloned (Comment) Organism
gene ald, genetic organization of the aldR-ald loci and their flanking genes Mycobacterium tuberculosis
gene ald, genetic organization of the aldR-ald loci and their flanking genes Mycobacterium marinum
gene ald, genetic organization of the aldR-ald loci and their flanking genes Mycolicibacterium smegmatis

Inhibitors

Inhibitors Comment Organism Structure
1-(isonicotinamido)-N2,N4-bis(benzo[d]thiazol-2-yl)azetidine-2,4-dicarboxamide
-
 Mycobacterium tuberculosis
2-ethyl-N-phenethyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-amine the molecule shows activity against nutrient-starved nonreplicating Mycobacterium tuberculosis, resulting in a 2.7 log reduction of bacterial loads at 0.010 mg/ml, and is shown to be more potent than the first-line antitubercular drugs, isoniazid and rifampicin, at the same dose. compound is cytotoxic Mycobacterium tuberculosis
4-(furan-2-ylmethylene)-1-phenylpyrazolidine-3,5-dione the compound exhibited potent antitubercular activity against log-phase cultures of Mycobacterium tuberculosis with a MIC of 0.0245 mM, but is found to be less active than the lead compound 1-(4-chlorophenyl)-4-(4-hydroxy-3-methoxy-5-nitrobenzylidene) pyrazolidine-3,5-dione (CD59). The compound is cytotoxic Mycobacterium tuberculosis
additional information development and optimization of compounds that inhibits the enzyme and can act as anti-tuberculosis drug, overview Mycobacterium tuberculosis

KM Value [mM]

KM Value [mM] KM Value Maximum [mM] Substrate Comment Organism Structure
0.009 0.098 NADH pH and temperature not specified in the publication Mycobacterium tuberculosis
0.31
-
 NAD+ pH and temperature not specified in the publication Mycobacterium tuberculosis
0.76 2.8 pyruvate pH and temperature not specified in the publication Mycobacterium tuberculosis
14 16 L-alanine pH and temperature not specified in the publication Mycobacterium tuberculosis
35 2900 NH3 pH and temperature not specified in the publication Mycobacterium tuberculosis

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
L-alanine + H2O + NAD+ Mycobacterium tuberculosis
-
 pyruvate + NH3 + NADH + H+
-
 r
L-alanine + H2O + NAD+ Mycobacterium marinum
-
 pyruvate + NH3 + NADH + H+
-
 r
L-alanine + H2O + NAD+ Mycolicibacterium smegmatis
-
 pyruvate + NH3 + NADH + H+
-
 r
L-alanine + H2O + NAD+ Mycobacterium sp. HE5
-
 pyruvate + NH3 + NADH + H+
-
 r
L-alanine + H2O + NAD+ Mycobacterium marinum ATCC BAA-535
-
 pyruvate + NH3 + NADH + H+
-
 r
L-alanine + H2O + NAD+ Mycolicibacterium smegmatis ATCC 700084
-
 pyruvate + NH3 + NADH + H+
-
 r
L-alanine + H2O + NAD+ Mycobacterium tuberculosis H37Rv
-
 pyruvate + NH3 + NADH + H+
-
 r
L-alanine + H2O + NAD+ Mycobacterium tuberculosis ATCC 25618
-
 pyruvate + NH3 + NADH + H+
-
 r
L-alanine + H2O + NAD+ Mycolicibacterium smegmatis mc(2)155
-
 pyruvate + NH3 + NADH + H+
-
 r

Organism

Organism UniProt Comment Textmining
Mycobacterium marinum B2HKV6
-
-
Mycobacterium marinum ATCC BAA-535 B2HKV6
-
-
Mycobacterium sp. HE5
-
-
-
Mycobacterium tuberculosis P9WQB1
-
-
Mycobacterium tuberculosis ATCC 25618 P9WQB1
-
-
Mycobacterium tuberculosis H37Rv P9WQB1
-
-
Mycolicibacterium smegmatis A0QVQ8 Mycobacterium smegmatis
-
Mycolicibacterium smegmatis ATCC 700084 A0QVQ8 Mycobacterium smegmatis
-
Mycolicibacterium smegmatis mc(2)155 A0QVQ8 Mycobacterium smegmatis
-
no activity in Mycobacterium africanum
-
 Mycobacterium africanum does not to produce Ald due to a frameshift mutation within the ald gene
-
no activity in Mycobacterium bovis
-
 Mycobacterium bovis does not to produce Ald due to a frameshift mutation within the ald gene
-
no activity in Mycobacterium microti
-
 Mycobacterium microti does not to produce Ald due to a frameshift mutation within the ald gene
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
glyoxylate + NH3 + NADH + H+ the enzyme catalyzes the reductive amination of glyoxylate to glycine, but not the reverse reaction Mycobacterium tuberculosis glycine + NAD+
-
 ir
glyoxylate + NH3 + NADH + H+ the enzyme catalyzes the reductive amination of glyoxylate to glycine, but not the reverse reaction Mycolicibacterium smegmatis glycine + NAD+
-
 ir
glyoxylate + NH3 + NADH + H+ the enzyme catalyzes the reductive amination of glyoxylate to glycine, but not the reverse reaction Mycobacterium sp. HE5 glycine + NAD+
-
 ir
glyoxylate + NH3 + NADH + H+ the enzyme catalyzes the reductive amination of glyoxylate to glycine, but not the reverse reaction Mycolicibacterium smegmatis ATCC 700084 glycine + NAD+
-
 ir
glyoxylate + NH3 + NADH + H+ the enzyme catalyzes the reductive amination of glyoxylate to glycine, but not the reverse reaction Mycobacterium tuberculosis H37Rv glycine + NAD+
-
 ir
glyoxylate + NH3 + NADH + H+ the enzyme catalyzes the reductive amination of glyoxylate to glycine, but not the reverse reaction Mycobacterium tuberculosis ATCC 25618 glycine + NAD+
-
 ir
glyoxylate + NH3 + NADH + H+ the enzyme catalyzes the reductive amination of glyoxylate to glycine, but not the reverse reaction Mycolicibacterium smegmatis mc(2)155 glycine + NAD+
-
 ir
L-alanine + H2O + NAD+
-
 Mycobacterium tuberculosis pyruvate + NH3 + NADH + H+
-
 r
L-alanine + H2O + NAD+
-
 Mycobacterium marinum pyruvate + NH3 + NADH + H+
-
 r
L-alanine + H2O + NAD+
-
 Mycolicibacterium smegmatis pyruvate + NH3 + NADH + H+
-
 r
L-alanine + H2O + NAD+
-
 Mycobacterium sp. HE5 pyruvate + NH3 + NADH + H+
-
 r
L-alanine + H2O + NAD+
-
 Mycobacterium marinum ATCC BAA-535 pyruvate + NH3 + NADH + H+
-
 r
L-alanine + H2O + NAD+
-
 Mycolicibacterium smegmatis ATCC 700084 pyruvate + NH3 + NADH + H+
-
 r
L-alanine + H2O + NAD+
-
 Mycobacterium tuberculosis H37Rv pyruvate + NH3 + NADH + H+
-
 r
L-alanine + H2O + NAD+
-
 Mycobacterium tuberculosis ATCC 25618 pyruvate + NH3 + NADH + H+
-
 r
L-alanine + H2O + NAD+
-
 Mycolicibacterium smegmatis mc(2)155 pyruvate + NH3 + NADH + H+
-
 r
additional information Ald catalyzes the reductive amination reaction faster and more efficiently than the oxidative deamination reaction Mycobacterium tuberculosis ?
-
-
additional information Ald catalyzes the reductive amination reaction faster and more efficiently than the oxidative deamination reaction Mycobacterium tuberculosis H37Rv ?
-
-
additional information Ald catalyzes the reductive amination reaction faster and more efficiently than the oxidative deamination reaction Mycobacterium tuberculosis ATCC 25618 ?
-
-

Subunits

Subunits Comment Organism
homohexamer
-
 Mycobacterium tuberculosis

Synonyms

Synonyms Comment Organism
ALD
-
 Mycobacterium tuberculosis
ALD
-
 Mycobacterium marinum
ALD
-
 Mycolicibacterium smegmatis
ALD
-
 Mycobacterium sp. HE5
NAD(H)-dependent L-alanine dehydrogenase
-
 Mycobacterium tuberculosis
NAD(H)-dependent L-alanine dehydrogenase
-
 Mycobacterium marinum
NAD(H)-dependent L-alanine dehydrogenase
-
 Mycolicibacterium smegmatis
NAD(H)-dependent L-alanine dehydrogenase
-
 Mycobacterium sp. HE5

pH Optimum

pH Optimum Minimum pH Optimum Maximum Comment Organism
7 7.5 reductive amination Mycobacterium tuberculosis
10 11 oxidative deamination Mycobacterium tuberculosis

Cofactor

Cofactor Comment Organism Structure
NAD+
-
 Mycobacterium tuberculosis
NAD+
-
 Mycobacterium marinum
NAD+
-
 Mycolicibacterium smegmatis
NAD+
-
 Mycobacterium sp. HE5
NADH
-
 Mycobacterium tuberculosis
NADH
-
 Mycobacterium marinum
NADH
-
 Mycolicibacterium smegmatis
NADH
-
 Mycobacterium sp. HE5

IC50 Value

IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
0.00182
-
 pH and temperature not specified in the publication Mycobacterium tuberculosis 2-ethyl-N-phenethyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-amine
0.00383
-
 pH and temperature not specified in the publication Mycobacterium tuberculosis 1-(isonicotinamido)-N2,N4-bis(benzo[d]thiazol-2-yl)azetidine-2,4-dicarboxamide
0.00814
-
 pH and temperature not specified in the publication Mycobacterium tuberculosis 4-(furan-2-ylmethylene)-1-phenylpyrazolidine-3,5-dione

Expression

Organism Comment Expression
Mycobacterium marinum regulation mechanism of ald expression by the AldR transcription factor in response to alanine availability, model for the regulation of ald expression by AldR, overview additional information
Mycolicibacterium smegmatis regulation mechanism of ald expression by the AldR transcription factor in response to alanine availability, model for the regulation of ald expression by AldR, overview additional information
Mycobacterium tuberculosis regulation mechanism of ald expression by the AldR transcription factor in response to alanine availability, model for the regulation of ald expression by AldR, overview. AldR exerts its regulatory effect on ald expression by binding AldR binding sites bearing a consensus sequence of GA/T-N2-NWW/WWN-N2-T/AC (W = A or T, /= or) in Mycobacterium tuberculosis. Three-dimensional structure of AldR and phylogenetic analysis of AldRs from mycobacteria additional information
Mycobacterium marinum expression of the ald gene is upregulated in Mycobacterium marinum during longterm granulomatous infection in its host up
Mycolicibacterium smegmatis hypoxic induction of ald, which is independent of the DevSR (DosSR) two-component system, a major regulatory system involved in oxygen and NO sensing in mycobacteria up
Mycobacterium tuberculosis hypoxic induction of ald, which is independent of the DevSR (DosSR) two-component system, a major regulatory system involved in oxygen and NO sensing in mycobacteria. Expression of the ald gene is upregulated in Mycobacterium tuberculosis under nutrient starvation and energy-limiting conditions. The enzyme is strongly induced by the nitric oxide (NO) donor diethylenetriamine/NO, and in vivo during initial lung infection in mice up

General Information

General Information Comment Organism
evolution distribution of Alds in mycobacteria, phylogenetic analysis and tree, overview. Alds of slow-growing mycobacteria are mostly distinct from those of fast-growing mycobacteria Mycobacterium sp. HE5
evolution distribution of Alds in mycobacteria, phylogenetic analysis and tree, overview. Alds of slow-growing mycobacteria are mostly distinct from those of fast-growing mycobacteria. Structure of Ald and phylogenetic relevance of mycobacterial Alds Mycobacterium tuberculosis
evolution distribution of Alds in mycobacteria, phylogenetic analysis and tree, overview. Alds of slow-growing mycobacteria are mostly distinct from those of fast-growing mycobacteria. Structure of Ald and phylogenetic relevance of mycobacterial Alds Mycobacterium marinum
evolution distribution of Alds in mycobacteria, phylogenetic analysis and tree, overview. Alds of slow-growing mycobacteria are mostly distinct from those of fast-growing mycobacteria. Structure of Ald and phylogenetic relevance of mycobacterial Alds Mycolicibacterium smegmatis
malfunction an ald mutant of Mycolicibacterium smegmatis is much more sensitive to the bcc1 complex inhibitor Q203 than the isogenic wild-type strain. Another ald mutant of Mycolicibacterium smegmatis reportedly displays decreased survival under oxygen depletion conditions compared with the wild-type strain. When Mycolicibacterium smegmatis strains are treated with KCN under aerobic conditions, expression of the ald gene in a bd quinol oxidase mutant strain of Mycolicibacterium smegmatis expressing only the aa3 cytochrome c oxidase as a terminal oxidase is more induced than that in the corresponding wild-type strain expressing both terminal oxidases. Reduced functionality of the ETC, rather than direct regulation of ald by an O2-sensing regulatory system, is most relevant to hypoxic induction of ald expression Mycolicibacterium smegmatis
malfunction the inactivation of ald in Mycobacterium tuberculosis confers a low level of DCS resistance. The mechanism underlying DCS resistance resulting from ald inactivation is suggested as follows: Mycobacterium tuberculosis strains lacking the functional Ald cannot convert L-alanine to pyruvate, resulting in an increase in cellular levels of L-alanine. As DCS is a competitive inhibitor of alanine racemase, inhibition of alanine racemase by DCS might be overcome by increased concentrations of L-alanine that is a substrate of alanine racemase Mycobacterium tuberculosis
metabolism regulation mechanism of ald expression by the AldR transcription factor in response to alanine availability, model for the regulation of ald expression by AldR, overview Mycobacterium tuberculosis
metabolism regulation mechanism of ald expression by the AldR transcription factor in response to alanine availability, model for the regulation of ald expression by AldR, overview Mycobacterium marinum
metabolism regulation mechanism of ald expression by the AldR transcription factor in response to alanine availability, model for the regulation of ald expression by AldR, overview Mycobacterium sp. HE5
metabolism regulation mechanism of ald expression by the AldR transcription factor in response to alanine availability, model for the regulation of ald expression by AldR, overview. AldR exerts its regulatory effect on ald expression by binding AldR binding sites (O1, O2, O3, and O4) bearing a consensus sequence of GA/T-N2-NWW/WWN-N2-T/AC (W = A or T; / = or) in both Mycolicibacterium smegmatis. Three-dimensional structure of AldR and phylogenetic analysis of AldRs from mycobacteria Mycolicibacterium smegmatis
physiological function enzyme Ald is implicated in resistance of Mycobacterium tuberculosis to the second-line drug D-cycloserine (DCS). DCS is known to inhibit two enzymes, alanine racemase and D-alanine-D-alanine ligase Mycobacterium tuberculosis
physiological function enzyme Ald is suggested to primarily play a biosynthetic role by catalyzing the reductive amination of pyruvate to alanine as judged by the very small Keq for the oxidative deamination reaction Mycobacterium tuberculosis
physiological function enzyme Ald seems to play a crucial role in the growth and survival of the organism under severe respiration-inhibitory conditions such as the inhibitory condition of both the bcc1-aa3 branch and bd quinol oxidase of the respiratory ETC Mycolicibacterium smegmatis